Cancer is a multi-step process caused by genetic abnormalities in proto-oncogenes and tumor suppressor genes. A highly specific and effective form of cancer therapy may be to target the repair, replacement or inactivation of oncogenes. Indeed, we and others have shown that the inactivation of a single oncogene can induce sustained tumor regression. However, we have also shown that tumors can escape dependence upon oncogenes. Now, to better interrogate the mechanisms by which oncogenes initiate and sustain tumorigenesis, we have generated a transgenic model in which we can temporally regulate, alone or in combination the expression of oncogenes, to study in vivo the kinetics of oncogene induced tumor regression upon oncogene inactivation. We have begun to use this strategy to examine how oncogene inactivation induces tumor regression, the role of host immune mechanisms to mediate this tumor regression and the genetic mechanisms by which cancers escape dependence upon oncogenes. We have obtained several potentially important preliminary results. First, we have found that when tumors are transplanted into immune compromised hosts, oncogene inactivation is much less capable of inducing tumor regression. These results suggest that immune mechanisms play a key role in mediating tumor regression upon oncogene inactivation. Second, we have used Spectral Karyotypic Analysis (SKY) and CGH Microarrays to demonstrate that tumors that escape dependence upon oncogenes have acquired novel chromosomal translocations. Our expectation is that both cell extrinsic and intrinsic mechanisms are involved tumor escape from oncogene dependence. In some cases, these mechanisms may converge. Thus, there are likely to be genetic events that impair the response of tumor cells to a host mediated suppression of tumorigenesis.